Substituted benzoquinones and process for their production



Patented May 29, 1945 SUBSTITUTED 'BENZO U NonEs AND PROG- ESS FOR THEIR PRODUCTION Max Tishler, Raliw'ay, N. .I., assig-norto Merck & 00,, Inc., Rahway, N. J., a corporation of- New Jersey NoDrawing. Application April 6, 1940,

. Serial No. 328,264

2 Claims. (Cl. 260-396) This invention relates to alkyl substituted 1,4- benzoquinone, alkyl substituted 1,4-n-aphthoquinone, derivatives and intermediates, more par- R ticularly those containing a .phytyl residue, and process for their production. X Z

These compounds are important as therapeutic Y N R1 agents or as intermediate products. One of them, i I 2,5,6-trimethyl-3-phytyl-l,4-benzoquinone is re-- R1 f Na I lated to and can e converted into alpha-towhere R and R1 are a-cyl radicals and R2 is an copherol which possesses vitamin Eactivity. Analkyl radical. The alkali metal salt of the hyother of them, 2-met y13-p yty p droquinone' may also 'be made directly from the 311 1 s the antihemorrhagi prin ip ,v hydroquinone 'by treatment with an alkali metal min K1. alcoholate. 7

I have found a t -a y -1,4-benzohydro The. following examples are given by wayof ilquinone and 2-alkyl-1,4-nEP th0hyd Oquin e relustration and not of limitation: react through their alkali metal salts with phy'tyl EXAMPLE I halides in nonpolar solvents such as ether, or benzene, to give the corresponding 3-'phytyl-1,4- 2.5.fi ri hy' -z i/tyl-1,4-b1enzoqui 0 hydroquinon'es which are readily oxidizable to the l 3.04 gm of 5 s trimethylbenzohydroquinone correspopding quinones' The reactions may be are suspended lOO cc. of dry benzene and the summa'nzed thus: mixture stirred and heated on a steam bath. A 011 OH gentle stream of nitrogen is allowed to pass over the mixture during thewarming and the subs'e- X X quent reaction. To the stirred mixture are added,

drop'wise; 4.6 cc. of an alcoholic solution of sodi- Y Y um methylate contaming 1 gm. of sodium in 10 H cc, of absolute methanol. During this addition where and Y may be hydrogen, and alkyl; or

1 and isolated and require no unusual precautions during such operations. The diacetates may be prepared by the reduction of the appropriate quinones in the .presence of acetic anhydride and anhydrous sodium acetate.

The alkali metal salt of the desired hydro- 1 quinone is readily derived from the diacetate by 66 heating with a solution cQntain-i-ngan alkali metal alcoholate as, for example:

the mixture becomes purple. When all the sodium' methylate solution has been added, the mixture is boiled and stirred under reflux for about "one hour. "7. 2 gm. of phytyl bromide are added, dropand the/mixture refluxed for 8 hours. The mixture becomes deep red, and anew turbidity occurs. The mixture is then added to a mixture of ice and about 460 60.01? per cent sulfuric-acid, shaken, and the benzene layer is separated, The benzene, solution is dried over anhydrous sodium sulfate, filtered, and the filtrate aerated in order -to oxidize the hydroquinone to the quinone, The

benzene solution is then poured through a tower of silicic acid. The uppermost layer of the tower consistsprincipally of unchanged 2,5;6-trimethylbenzoqu'inone and is separated and discarded. The middle layer is eluted with ether and this chromatographic adsorption is repeated four. times. vThe product, '2;5,-6 -trimethyl-3-phytyl concentrating the last ether-eluate.

The product may also be isolated by the'm'e'thod Of Fieser, J. A. C. S., 61:34'67 (1939), or through benzoquinone is obtained substantially pure by the diacetate which may be obtained by reduc-,

tively acety-lating the crude product. The diacetate or the crude 'mixtureis then fractionally crystallized from methyl alcohol whereupon the diacetate of 2,5,6-trimethyl-3-phytyl-benzohy ,droquinone is obtained, melting point 565 C. 3

Analysis Cale. 77.04 10.51 Found 76.95 10.37

The diacetate is converted to the quinone by usual procedures of hydrolysis using either alkali or methylmagnesium iodide and oxidizing the hydroquinone by means of air, silver. oxide, ferric chloride, etc.

2,5,6etrimethyl-3-phytyl-benzoquinone is obtained as a bright yellow oil.

Analysis Calc 81.24 11.22 Found T 81.04 11.00

Absorptiou spectrum: Em =17.1 at 2640. I p The quinone is alsocharacterized by the fact that on reduction in acid medium 'alpha-tocopherol is formed. 1

' EXAMPLE II 2m t yl-smegma,4-n phmog1im n gm. of 2-methyl-1,4-naphthohydroquinone diacetate are. dissolved in 100 cc. dry :benzene and, while stirring and warming the mixture in the presence of nitrogen, 4.5-cc. ofpercent sodium methylate in methanol are added, dropwise. The mixture is refluxed for about 3 hours, during which a green solid separates. .82 gm. of phytyl bromide in 10cc. of benzene are added and the mixture is boiled and stirred for about 6 hours. Meanwhile, the green solid disappears.

andv a greenish-white .turbidity occur in the mixture of which the supernatant liquid is orange. The mixture is, poured into a mixture of cracked ice and dilute hydrochloric acid and the benzene. layer separated. The benzene layer is washed with water,-concentrated, and the reddish-orange residue is taken up in petroleum ether. V

The product may .be' isolated by chromato graphic adsorption, .by the method oLFieser :or through the diacetate as described in Example I.

3 Rh m-L -n h hohyd o nq diacetate melts at 60 C. and is identical with the diacetate prepared from natural vitamin K Y 2-methyl-3-phytyl-1,4-naphthoquinon is a golden yellow oil. 1 V

V Analysis Galois. I82.61 round 82.52 10.30

Itislidentical with natural vitamin K1. as its color test with sodium ethylate (Dam, Karrer and others, Helv. 22:310- (1939)), its absorption spectra, its, conversion to the diacetate of the dihydro form, and its antihemorrhagic activity indicate.

EXAMPLE III 2-ethyl-3-phytyZ-1,4-naphthohydroquinone a 0.83 gm. of powdered sodium are suspended, in 50cc. of dry benzene. Tothis suspension is added,

with stirring, 4 equivalents of absolute ethanol and the mixture is left to stand overnight. While the mixture is kept under nitrogen, 9.2 gm. of

. 2-ethyl-1,4-naphthohydroquinone diacetate (prea few minutes.

pared by the reductive acetylation of 2-ethyllA- naphthoquinone) in 50 cc. of dry benzene are added. A bright green precipitate forms within The mixture is stirred and refluxed for one hour, and then 13 gm. of phytyl bromide are added. The mixture is stirred and refluxed during which sodium bromide separates and the green color becomes less intense. The

mixture is then allowed to stand overnight at room temperature. A test portion of the mixture is now neutral to litmus indicating completion of the reaction. The mixture is poured into "ice water, extracted with petroleum ether, the I extract dried over anhydrous sodium sulfate and On hydrolysis with methylmagnesium-iodide and concentrated to a reddish-orange oil, which, like natural vitamin K1, gives a transient purple color with sodium ethylat'e.

As the resultant oil, 2-ethyl-3-phytyl-1,4- naphthohydroquinone, is not crystalliz'able and isunstable to heat (and, is therefore'not distillable even under extremely low pressure), it,

is preferably isolated in the form of its diacetate which is obtained by reductive acetylation in the usual manner, The diacetate may be purifiedby solution in ether, concentration to an oil under vacuum and distillation at 10- mm. at 1G. in a molecular still. 2-ethyl-3-phytyl-1,4-naph thohydroquinone diacetate is a pale yellow, oily,

noncrystallizable liquid:

Analysis c.1c. '--72.2s 9.72 15.65 Found 72.48 9.84 15.44

subsequent oxidation by air or silver oxide as described in Example I, 2-ethyl-3-phytyl-l,4- naphthoquinone is obtained as a yellow, mobile liquid; The product givesthe samecharacteristic color reaction with sodium methylate as does ,2-methyl-3-phytyl- 1,4-naphthoquinone.

Analysis Cale 82.7 10.32 Found 82.57 10.35

I claim:

1. In a, process for the production of 2,5,6-tr'i- I methyl-3-phytyl-1,4-benzoquinone,' the steps comprising treating 2,5,6-t rimethyl-1,4 benzo- .hydroquinone with an alkali metal alcoholate and reactingthe hydroquinone salt iii an alkali metal thus formed With phytylhalide in the presence of'a nonpolar solvent, i I I 2. In a process for the'production of 2;5,6-trimethyl-3-phytyl-1,4-benzoquinone, comprising treating 2,5,6-trimethyl-l,4-benzo-- hydroquinone diacetate with an alkali metal alcoholate and reacting the hydroquinone salt of an alkalimetal'thus formed with phytyl halide in the" presence' of a nonpolar solvent.

. MAX

the steps 

